Phase 1 Study of Oral TP-1454

• ClinicalTrials.gov Identifier: NCT04328740
• Recruitment Status: Active, not recruiting
• First Posted: March 31, 2020
• Last Update Posted: November 22, 2022
• Sponsor: Sumitomo Pharma Oncology, Inc.
• Information provided by (Responsible Party): Sumitomo Pharma Oncology, Inc.

Study Description

Brief Summary:

This study will evaluate the safety and tolerability of oral TP-1454 in patients with advanced metastatic or progressive solid tumors, alone and in combination with Ipilimumab and Nivolumab.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor; Advanced/ Metastatic Renal Cell Carcinoma (RCC); Microsatellite Iinstability-high (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer (CRC); Non-Small Cell Lung Cancer (NSCLC)	Drug: TP-1454 monotherapy; Drug: TP-1454 combination therapy	Phase 1

Detailed Description:

Primary Objectives During Dose Escalation:

• To establish the MTD and/or Recommended Phase 2 Dose (RP2D) of orally administered TP-1454 monotherapy in patients with advanced metastatic solid tumors
• To establish the MTD and/or RP2D of orally administered TP-1454 in combination with ipilimumab and nivolumab in patients with advanced/ metastatic renal cell carcinoma (RCC) and patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), who are eligible per FDA approval of ipilimumab and nivolumab by indication for the protocol- defined regimen

Secondary Objectives During Dose Escalation:

• To establish the pharmacokinetic (PK) profile of orally administered TP-1454 alone and in combination with ipilimumab and nivolumab
• To observe patients for any evidence of antitumor activity of TP 1454 alone and in combination with ipilimumab and nivolumab by objective radiographic assessment
• To assess the safety and tolerability of oral TP-1454 administered as monotherapy and in combination with ipilimumab and nivolumab in the defined patient populations

Primary Objectives During Dose Expansion:

• To evaluate the preliminary antitumor activity, by objective radiographic assessment, of TP-1454 in combination with ipilimumab and nivolumab in patients with mNSCLC expressing PD-L1 (≥1% as determined by an FDA-approved test) with no EGFR or ALK genomic tumor aberrations
• To establish the RP2D of orally administered TP-1454 in combination with ipilimumab and nivolumab in the defined patient population

Secondary Objectives During Dose Expansion:

• To assess the safety and tolerability of oral TP-1454 in combination with ipilimumab and nivolumab in the defined patient population

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 44 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, First-in-human, Open-label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP 1454 Alone and in Combination With Ipilimumab and Nivolumab
• Actual Study Start Date: July 8, 2020
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: October 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Monotherapy; TP-1454	Drug: TP-1454 monotherapy; Flat dose once or twice daily, alone
Experimental: Combination Therapy; TP-1454, ipilimumab and nivolumab	Drug: TP-1454 combination therapy; Flat dose once or twice daily, in combination with ipilimumab and nivolumab

Outcome Measures

Primary Outcome Measures :

1. During Dose Escalation: Incidence of dose-limiting toxicities (DLTs) [ Time Frame: 21 or 28 days ]
   A DLT is defined as a drug-related toxicity that is observed to occur within the first 21 or 28 days of treatment depending on which arm the patient is enrolled in (monotherapy 28 days; combination 21 days).
2. During Dose Escalation: Determine maximum tolerated dose (MTD) [ Time Frame: 28 months ]
   MTD will be determined based upon toxicity grades which are defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.
3. During Dose Escalation: Recommended Ph 2 dose of TP-1454 [ Time Frame: 28 months ]
   To establish the recommended Ph 2 dose (RP2D) for future studies with TP-1454. MTD, PK and PD data to be reviewed.
4. During Dose Expansion: Determine the preliminary antitumor activity of TP-1454 in combination with ipilimumab and nivolumab [ Time Frame: 18 months ]
   Determine the preliminary antitumor activity of TP-1454 in combination with ipilimumab and nivolumab in terms of objective response rate (ORR) in patients with mNSCLC expressing PD-L1 (≥1% as determined by an FDA-approved test) with no EGFR or ALK genomic tumor aberrations according to RECIST v 1.1 and iRECIST.
5. During Dose Expansion: Recommended Ph 2 dose of TP-1454 in combination with ipilimumab and nivolumab [ Time Frame: 18 months ]
   Establish the Recommended Ph2 dose for future studies of orally administered TP-1454 in combination with ipilimumab and nivolumab in the defined population. MTD, PK and PD data will be reviewed.

Secondary Outcome Measures :

1. During Dose Escalation: Determine antitumor activity of TP-1454. [ Time Frame: 28 months ]
   Objective radiographic assessment to be performed to determine antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST criteria v 1.1.
2. During Dose Expansion: Asses the safety and tolerability of TP-1454 [ Time Frame: 18 months ]
   Assess the safety and tolerability of oral TP-1454 in combination with ipilimumab and nivolumab in the defined patient population. MTD, PK and PD data will be reviewed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Dose Escalation: Have a histologically confirmed diagnosis of a) advanced metastatic or progressive solid tumor, who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition (Monotherapy Arm) b) advanced/metastatic renal cell carcinoma (RCC) and patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), who are eligible per FDA approval of ipilimumab and nivolumab by indication for the protocol- defined regimen (combination arm).
2. Dose Expansion: Have a histologically confirmed diagnosis of mNSCLC expressing PD-L1 (≥1% as determined by an FDA-approved test) with no EGFR or ALK genomic tumor aberrations, and who are eligible per FDA approval of ipilimumab and nivolumab by indication for the protocol-defined regimen
3. Naïve to prior treatment with any PD1 or CTLA-4 inhibitor (Combination Arm Only)
4. Have measurable as outlined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
6. Have a life expectancy ≥3 months
7. Be ≥18 years of age
8. Have a negative pregnancy test (if female of childbearing potential)

9. Have acceptable liver function:

   1. Bilirubin ≤1.5x upper limit of normal (ULN) (unless associated with Gilbert syndrome)
   2. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase ≤2.5x ULN* *If liver metastases are present, then ≤ 3x ULN is allowed. ** For patients who will receive ipilimumab and nivolumab in combination with TP-1454 then ≤ 3X ULN is allowed
10. Have acceptable renal function: calculated creatinine clearance ≥30 mL/min (using Cockcroft Gault formula)

11. Have acceptable hematologic status:

    1. Granulocyte ≥1500 cells/mm3
    2. Platelet count ≥100,000 (plt/mm3)
    3. Hemoglobin ≥8 g/dL

12. Have acceptable coagulation status:

    1. Prothrombin time (PT) within 1.5x normal limits
    2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits

13. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation and for at least 3 months (males) and 6 months (females) after the last study drug dose.

    Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

14. Have read and signed the Institutional Review Board (IRB)-approved informed consent form (ICF) prior to any study-related procedure. (In the event that the patient is rescreened for study participation or a protocol amendment alters the care of an ongoing patient, a new ICF must be signed.)

Exclusion Criteria:

1. New York Heart Association Class III or IV cardiac disease, or myocardial infarction, severe unstable angina, coronary/peripheral artery bypass graft, congestive heart failure within the past 6 months or evidence of ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1/Day 1
2. Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of >450 msec in men and >470 msec in women
3. Have a seizure disorder requiring anticonvulsant therapy
4. Have untreated central nervous system (CNS) metastases including carcinomatous meningitis. Patients with definitively treated (radiotherapy or surgery) CNS metastases may be eligible if asymptomatic and not receiving corticosteroids in excess of prednisone 10 mg (or equivalent) per day for ≥2 weeks before first dose of TP-1454
5. Have hypoxemia (defined as resting O2 saturation of ≤90% breathing room air)
6. Have symptomatic interstitial lung disease or radiographic changes in the lungs that may make detection, diagnosis, or treatment of drug-induced pneumonitis difficult
7. Have undergone major surgery within 2 weeks prior to Cycle 1/Day 1
8. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
9. Are pregnant or nursing
10. Received treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives, whichever occurs first, prior to study entry (6 weeks for nitrosoureas or mitomycin C)
11. Are unwilling or unable to comply with procedures required in this protocol
12. Have known infection with human immunodeficiency virus, hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible
13. Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
14. Are currently receiving any other investigational agent
15. Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
16. Have malabsorption conditions (eg, Crohn's disease, etc) or have undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption
17. Require systemic corticosteroids greater than the equivalent of 10mg of prednisone or equivalent alternative steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents (e.g., cyclosporine or methotrexate) (patients receiving combination therapy only)
18. Have a history of malignancy within the past 24 months except curatively treated in situ cancers

19. Have active, known, or suspected autoimmune disease with the exception of (patients receiving combination therapy only):

    • Type I diabetes mellitus
    • Hypothyroidism only requiring hormone replacement
    • Skin disorders not requiring systemic treatment, eg, vitiligo, alopecia, or psoriasis
20. Have known EGFR mutations or ALK alterations that are sensitive to targeted therapy in NSCLC tumor types (patients receiving combination therapy only)
21. Have ≥Grade 2 peripheral neuropathy (patients receiving combination therapy only)

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Arizona

Phoenix, Arizona, United States, 85054

United States, California

University of Southern California - Norris Cancer Center and Hoag Memorial Hospital

Los Angeles, California, United States, 90033 and 92663

United States, Florida

Mayo Clinic Jacksonville

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic Rochester

Rochester, Minnesota, United States, 55905

United States, Nevada

Comprehensive Cancer Center of Nevada

Las Vegas, Nevada, United States, 89169

United States, Texas

Texas Oncology Baylor Sammons Cancer Center

Dallas, Texas, United States, 75246

United States, Utah

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Sumitomo Pharma Oncology, Inc.

Investigators

• Study Director: Matt Hitron, MD; Sumitomo Pharma Oncology, Inc.

More Information

• Responsible Party: Sumitomo Pharma Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT04328740
• Other Study ID Numbers: TP-1454-101
• First Posted: March 31, 2020
• Last Update Posted: November 22, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sumitomo Pharma Oncology, Inc.:

Sumitomo Dainippon Pharma Oncology SDPO; Phase 1; Advanced Solid Tumors; Refractory

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Neoplasms by Site; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Kidney Diseases; Urologic Diseases